3 mono and 3, 16-diesters of delta5-androstene-3beta, 16alpha-diol-17 one and process for the production thereof



United States Patent 3 MONO AND 3,16-DIESTERS OF A -ANDROSTENE- 3fi,16a.-DIOL-17 ONE AND PROCESS FOR THE PRODUCTION THEREOF Allan Eugene Hydorn, Milltown, and James Riva Moetz, New Brunswick, N.J., assignors, by mesne assignments, to E. R. Squibb & Sons, Inc., New York, N.Y., a corporationof Delaware No Drawing. Filed Aug. 19, 1964, Ser. No. 390,723

8 Claims. (Cl. 260397.4)

This invention relates to a new method for preparing steroids and to certain new steroids prepared thereby; and, more particularly, to the preparation of new 3- monoesters and certain new 3,16-diesters of A -androstene-3B,l6a-diol-17-one from diesters of A -androstadiene-B,17-diol.

The process of this invention can be represented by the following equations, wherein R is an acyl group, preferably of a hydrocarbon carboxylic or dicarboxylic acid of less than twelve carbon atoms and R is the acyl group of a hydrocarbon dicarboxylic acid of less than twelve carbon atoms (e.g., malom'c, succinic, glutaric, and maleic acid) or a salt thereof, such as a salt with an alkali metal hydroxide, alkaline earth metal'hydroxide and amine:

To prepare the compounds of this invention, a diester of A -androstadiene-3B,17-diol, wherein the esterifying groups can be the same or different and preferably are acyl groups of hydrocarbon carboxylic or dicarboxylic acids of less than twelve carbon atoms, as exemplified by one of the alkane dicarboxylic acids mentioned hereinbefore, or a monocarboxylic acid such as the lower alkanoic acids (e.g., acetic, propionic, butyric, pentanoic, hexanoic, and octanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and o, m, and p-toluic acids), the monocyclic ar(lower alkanoic) acids (e.g., phenacetic and B-phenylpropionic acid), the monocyclic cycloalkane carboxylic acids, and the monocyclic cycloalkene carboxylic acids, is treated with a permanganate, such as an alkali metal permanganate (e.g., potassium permanganate) and dilute formic acid (such as 10% aqueous formic acid), preferably in the presence of an organic solvent, such as acetone, for the steroid reactant. The reaction surprisingly selectively oxidizes the 16,17-double bond to a glycol which undergoes immediate elimination of the unstable l7-hemiacylal to give the 16a-hydroxy-17-one, thereby yielding the new 3-monoesters of A -androstene-3fi,l6oc-diol-17-one of this invention.

These new 3-monoesters can, if desired, be further acylated, as by treatment with an acyl chloride or acid ice anhydride of one of the hydrocarbon dicarboxylic acids mentioned hereinbefore, preferably in the presence of a tertiary base, such as pyridine, to yield the new diesters of this invention; or can be hydrolyzed, as by treatment with methanolic sulfuric acid, to yield the known A -andr0stene-3B,16a-diol-17-one. The hemiesters thus formed can then be neutralized in the usual manner to yield the salts of this invention.

In addition to their use as intermediates, the new compounds of this invention are physiologically active substances, which have androgenic activity and hence can be administered in the same manner as and in lieu of known androgens, such as testosterone, for the treatment of conditions responding to androgenic agents.

The following examples illustrate the invention (all temperatures being in centigrade):

Example 1.A -andr0stene-3fl,16a-di0l-17-0ne 3-acetate 2 g. of A -androstadiene-3fi,l7-diol 3,17-diacetate (prepared by reacting 10 g. of A -androstene-3fl ol-l7- one acetate with 200 ml. of isopropenyl acetate and 1.5 g. of p-toluenesulfonic acid) in 60 ml. of acetone containing 3.3 ml. of 10% aqueous formic acid is mixed with a solution of 1.75 g. of potassium permanganate in ml. of water diluted to 58.4 ml. with acetone. The

' mixture is held at 2530 for 1.5 hours to giveabout 0.48 g. of pure A -androstene-3fl,l-6a-diol-l7 one 3-acetate, M.P. about 163-164? Similarly, if other 3,17-diesters are used in lieu of the diacetate as starting materials in the procedure of Example 1 the corresponding 3-monoesters of A -androstene- 3B,16o-diol-17-one are obtained. Thus, the 3,17-dipropionate and 3,17-dibenzoate of A -androstadiene-3fl,17- diol yield the 3-propionate and 3-benzoate of A -androstene-3 5,16a-diol-l7-one, respectively.

Example 3.-A -andr0stene-3 [3,1 6a-di0l-1 7-0ne 3-acetale, 16-hemisuccinate A solution of 100 mg. of A -androstene-3fi,16a-diol-17- one 3-acetate and 0.4 g. of succinic anhydride in 4 ml.

of dry pyridine is allowed to stand at room temperature for about 36 hours. The solution is diluted with about 40 ml. of water and made acidic by adding a sufficient quantity of 6 N sulfuric acid. The solid that separates is filtered and recrystallized from ethanol to give about 30 mg. of A -androstene-3B,16lx-diol-l7-one 3-acetate, IS-hemisuccinate, M.P. about 138441.

Example 4.A -andr0Stene-3B,16udi0l-17-0ne 3-acetate, 16-hemisuccinate sodium salt 4.5 mg. of A -androstene-3fl,16a-diol-17-one 3-acetate, l-6-hemisuccinate is dissolved in 0.02 ml. of 10% aqueous sodium carbonate solution and 0.18 ml. of warm water to give an approximately 2% aqueous solution of the sodium salt of A -androstene-3B,l6a-diol-l7-or1e 3-acetate, 16-hemisuccinate.

The invention may be variously otherwise embodied within the scope of the appended claims.

1. A steroid of the formula w MU wherein R is selected from the group consisting of the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, a hydrocarbon dicarboxylic acid of less than twelve carbon atoms, and alkali metal, alkaline earth metal or amine salts of'the latter; and R" is selected from the group consisting of hydrogen, the acyl radical of a hydrocarbon dicarboxylic acid of less than twelve carbon atoms and salts thereof.

2. A -androstene-3fi,l6u-diol-17-one B- acetate.

3. A -androstene-3fi,l6a-diol-17-one 3-acetate, 16-hemisuccinate.

4. The sodium salt of A -androstene3fl,16a-diol-17- one 3-acetate, l6-hemisuccinate.

5. A process for preparing the 3-monoesters of A an: drostene-3fi,l6'a-diol-17-one, which comprises reacting a 3,17-diester of Ai -amdrostadiene-Iifi,17-diol with an alkali metal permanganate and dilute formic acid.

. I What is claimed is:

wherein R is the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, and R" is the acyl radical of a hydrocarbon dicarboxylic acid of less than twelve carbon atoms or a salt thereof.

References Cited by the Examiner Aoki et al.: Chem. & Pharm. Bull., Japan, vol. 12, July 1964. V

Fieser et aL: Steroids, 1959, Reinhold Publishing Corp, New York, pages 527-528 relied on.

LEWIS GOTTS, Primary Examiner.

E. L. ROBERTS, Examiner. 

1. A STEROID OF THE FORMULA 